Summary Background Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). Methods In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. Findings The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart dis...

Objectives To discuss the features of study design and analysis which are necessary to derive valid Design Prospective study of 663 fetuses. ResultsThe selection of the sample and adequate sample size are of great importance. Prospective collection of data specifically for the purpose of deriving centiles is recommended. It is essential to use statistical methods that take proper account of the increasing variation among fetuses as pregnancy proceeds; such methods are described and illustrated. A study is described which meets the stated criteria for design and analysis, and from which new fetal size centile charts have been derived and are presented in subsequent papers.Conclusions Many published studies containing charts (standards) of fetal size are methodologically flawed. Research design and statistical analysis must adhere to sound principles for fitted centiles of size to be valid and so clinically relevant.

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Objective To construct new size charts for fetal head circumference, biparietal diameter and other head dimensions. Design A prospective, cross sectional study. Setting The routine ultrasound department of a London teaching hospital. Subjects The fetuses of 663 women seen in the routine antenatal booking clinic whose ultrasound and menstrual dates agreed within 10 days. Methods Fetuses were scanned once only for the purpose of the study at gestations between 12 and 42 weeks, when up to 20 dimensions were measured. For each measurement separate regression models were fitted to estimate the mean and standard deviation at each gestational age. Centiles were derived by combining these two regression models, assuming that the measurements have a normal distribution at each gestational age. Results A total of 594 fetuses had their biparietal diameter measured and their head circumference measured directly. Both head diameters were recorded for 587 fetuses and the circumference was also derived from these, as was the cephalic area. New charts are presented for biparietal diameter (both outer–outer and outer–inner), head circumference (directly measured and derived from diameters). The directly measured head circumferences were consistently (by about 1%) greater than those derived from measurement of the head diameters. The new charts are compared with previously published charts that are in wide use. Charts for occipitofrontal diameter, cephalic index and cephalic area are also presented. Conclusions We have constructed new size charts for the fetal biparietal diameter and for head circumference, both measured directly and derived from head diameters. We have demonstrated the difference between the size charts constructed from these two sets of values and hence the importance of using the appropriately derived chart when assessing the head circumference. The differences between the new charts for biparietal diameter and head circumference and previous ones may be largely due to methodological differences.